As colorectal cancer (CRC) remains one of the leading causes of cancer death new approaches are of vital importance to make critical inroads in reducing the burden of this lethal disease. Precision medicine holds enormous promise as advances in genomic research that were previously unimaginable now offer vast commercial potential and are rapidly being moved into clinical practice, even though critical questions remain to be addressed. Polygenic risk scores (PRS) that aggregate common genetic risk variants into a single score to predict disease are a key example. Broad accessibility, plummeting genotyping costs, and the need to account for the patient's individual risk profile to improve screening have provided transformative opportunities in personalized prevention. However, wide-scale clinical adoption of PRS raises key ethical and scientific challenges. Arguably one of the most critical challenge is the fact that current PRS are substantially more effective in predicting risk in individuals of European ancestry compared with other populations due to the Euro- centric bias in genetic research. Accordingly, we need to develop an unbiased PRS that predicts CRC risk in all major racial/ethnic groups. However, this is only the first step towards implementation, which also requires the evaluation of the optimal risk-stratified screening approach and development of risk communication tool among others. To address these needs, we will develop and validate an unbiased PRS for CRC across ethnic/racial minority groups to inform risk-stratified CRC screening (Aim 1a). We will augment the PRS with an environmental/ lifestyle risk score (ERS) to account for other risk factors (Aim 1b) and examine differential effects by age of onset (Aim 1c), given the alarming increase of early onset CRC. In Aim 2a we will determine the optimal CRC screening strategy given an individual's risk defined in Aim 1 using our microsimulation modeling by incorporating differences in CRC incidence and mortality rates by age, sex and race/ethnicity, and in risk factor distributions across racial/ethnic groups. In Aim 2b we will evaluate the cost-effectiveness of risk stratified screening compared with current screening guidelines. Finally, we will develop a risk communication tool (Aim 3a) and investigate potential dissemination issues of risk-stratified CRC screening across ethnic/racial minority groups (Aim 3b). Our trans-disciplinary research team, which includes a community advisory board, is uniquely set up to address these critical questions as we 1) have brought together all known racially/ethnically diverse CRC studies totaling to over 120,000 CRC cases and controls, 2) have strong expertise in developing comprehensive genetic and environmental risk scores in racially/ethnically diverse populations, 3) lead one of the most comprehensive decision models for cost-effectiveness analysis which has consistently been used to inform US screening guidelines and 4) have expertise in implementation science for genetic research in minorities. Addressing all aims is critical to avoid a sequential science in this rapidly moving field of precision medicine.